1. PO 2726; IAS; 20051 Vicriviroc (formerly SCH 417690): Antiviral Activity of a Potent New CCR5 Receptor Antagonist D. Schuermann, C. Pechardscheck, R. Rouzier, R. Nougarede, J. Reynes, G. Faetkenheuer, I. Ochlast, F. Raffi, C. Michelet, C. Hoffman, J. Klunke, S. Sprenger, J.J. van Lier, W. Greaves, A. Sansone

2. PO 2726; IAS; 20052 Vicriviroc Background  Small molecule inhibitor of the CCR5 receptor -Prevents entry of HIV into T-cells  Synergistic activity with existing antiretrovirals  Active against multi-drug/class resistant strains  Dose-limiting toxicity in animals was seizures -Seizure threshold 10-20 fold above clinical exposures  Rapid, complete absorption in most animals  Consistent PK; manageable drug interactions -Not p-Gp substrate; CYP3A4 substrate, not inhibitor or inducer -Boosted by ritonavir (RTV) [AUC x 5, Cmax x 3]

3. PO 2726; IAS; 20053 Study Objectives  To evaluate the safety, tolerability, PK, and antiviral activity of vicriviroc in CCR5-only HIV-infected individuals -Safety monitored by clinical condition, laboratory parameters, adverse event reporting, and ECGs -PK profile assessed on Day 1 and Day 14  Trough concentrations measured on Days 12-14 -Plasma HIV RNA measured on Days 1-7, 9,11,13-17, 21, 25, and 28

4. PO 2726; IAS; 20054 Study Design  Sequential, ascending dose cohorts  Subjects randomized within cohort to active:placebo (12:4) in double-blind fashion  Each cohort enrolled after safety evaluation at previous dose level was determined with at least 7 days separating dose levels  Subjects received 14 days of vicriviroc as monotherapy: 10 mg, 25 mg, and 50 mg BID  Days 1-7 & 12-14 completed as in-patient -Outpatient visits on Days 9, 11, 15-17, 21, 25, and 28

5. PO 2726; IAS; 20055 Patient Population  HIV-infected adults on no ART  Only CCR5-tropic virus detected  CD 4 count > 200 cells/µL; RNA 5000 – 200,000  No contraindicated disease  Baseline Characteristics: -Age: mean 38 years (range 25-53); 82% male -CD 4 count: mean 478 cells/µL (range 186-1121) -HIV RNA: mean 4.6 ± 0.5 log 10 -Characteristics well balanced across dose groups

6. PO 2726; IAS; 20056 a: n=11; b: n=48 477 b (122-1121) 384495600 a 431 CD4+ (cells/mm 3 ) 4.6 b (3.0-5.8) 4.84.44.3 a 4.7 HIV RNA (log10) 40/97/412/111/110/3 Gender (M/F) 38.0 (25-53) 37.736.839.038.7 Age (yrs) All Subjects n=49 50 mg BID n=11 25 mg BID n=13 10 mg BID n=12 Placebo n=13 Baseline Characteristics

7. PO 2726; IAS; 20057 Safety Results  Vicriviroc was well tolerated  No dose-related AEs -3 SAEs not related to dose or drug -Mild-moderate headache, diarrhea, nausea not dose-related  No changes in ECG or cardiac rhythm  No clinically significant changes in lab values

8. PO 2726; IAS; 20058 Pharmacokinetic Results  PK dose-proportional  Rapid absorption; clearance is dose independent  T 1/2 > 24 hours (mean range 28.7 – 32.8 h)  Minimal variability in absorption - % CV range from 21 to 35%  Steady state reached by day 12  2-fold accumulation by day 14  Extensive distribution in extravascular space - Large volume of distribution (770-960 L)  Trough concentration well above IC90 (3.9 ng/mL)

9. PO 2726; IAS; 20059 Antiviral Activity Placebo Vicriviroc 10MG Vicriviroc 25MG Vicriviroc 50MG Log 10 HIV-1 RNA Mean Change From Baseline -1.8 -1.6 -1.4 -1.2 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 post antiviral effect Dosing p=0.013* *10mg vs 50mg BID

10. PO 2726; IAS; 200510 Day 14 Virologic Response Rates 0 10 20 30 40 50 60 70 80 90 100 Placebo20 mg50 mg100 mg >0.5 log drop >1.0 log drop >1.5 log drop >2.0 log drop Overall % of the Treatment Group Daily Dose

11. PO 2726; IAS; 200511 Conclusions  Vicriviroc was well tolerated up to 100 mg daily for 14 days  PK supports once daily dosing in future trials -PK parameters were linear and predictable  Vicriviroc caused a 1.6 log drop in HIV RNA as 14 days of monotherapy in CCR5-infected subjects -50 and 100 mg daily doses showed similar activity  CD4 increases mirrored antiviral activity  Further development in combination regimens is on-going